The effects of cytosine phosphoguanine oligodeoxynucleotides (CPG ODNs) on immune response have been demonstrated for different vaccines; however, such information is limited for the vector-based Coronavirus disease 2019 (COVID-19). This paper aims to demonstrate the potential effect of CPG ODNs on immunological response against the vector-based COVID-19 vaccine on Balb/c mice using a JNJ-78436735 Ad26.COV2-S recombinant as a model vaccine. A total of 18 BALB/c mice clustered into six groups were used. All groups were observed for 14- and 28-days post immunization. Qualitative determination of IgG was performed using indirect Enzyme-Linked Immunosorbent Assay (ELISA) and qPCR for cytokine profiling. A significant (p ≤ 0.001) rise in antibody response was observed for groups 3 and 4, who also showed increased expression levels of Tumor Necrosis Factor (TNF) and Interferon Gamma (IFN-γ). Immunological parameters for toxicity were normal in all treatment groups. We conclude that supplementing vector-based COVID-19 vaccines with CpG ODNs has the potential to boost the body’s immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.